In general anesthetic agents depress the reponsiveness to adrenergic stimuli. Certain local and intravenous anesthetic agents alter the uptake and storage of norepinephrine (NE) at post ganglionic terminals in blood vessel walls. The overall aims of the proposed research are, one, to determine the mechanism of action of anesthetic agents on neurotransmitter storage vesicles from rat brain and, two, to continue studies of the actions of halothane and morphine on exocytotic release mechanism in peripheral blood vessels. The uptake of NE by neurons is characterized by two distinct and separable processes. One system transports amines from the synaptic cleft to the neuronal cytoplasm. This system is responsible primarily for termination of the actions of released NE. Inhibition of neuronal uptake does not cause significant transmitter depletion. Anesthetic agents in clinical use concentrations have little effect on this system. By contrast, the second uptake system, vesicular uptake, has as its main function the maintenance of transmitter stores. Etidocaine, morphine, fentanyl, and droperidol all cause increased efflux from these vesicular stores. Since efflux of NE occurs into the neuroplasm where the enzyme monoamine oxidase exists, the amine will become depleted. Storage vesicles isolated from rat brains display an in vitro NE uptake mechanism with properties that are kinetically and pharmacologically similar to peripheral neurons. We plan to use brain vesicles to determine whether anesthetic agents increase release or prevent reuptake of the transmitter. This question is clinically relevant because patients treated with reserpine or amphetamine have different anesthetic requirements. In blood vessels the emphasis will be on how halothane and morphine alter exocytotic release of NE. Thus endogenous NE and dopamine beta hydroxylase efflux will be measured. Comparison of the effects of these two anesthetic drugs on adrenergic neurotransmission in vascular smooth muscle is highly desirable because it remains undecided whether halothane, which causes hypotension, or morphine, which may cause hypertension, is the more suitable for patients with diminished circulatory reserve.